tbuckley/cabot-search huggingface dataset:
Abstract 1391: PBMC humanized mouse model for ImmunoOncology drug evaluation
Authors: Bin Xie, Hongkui Chen, Xin Hou, Danyi Wen
Journal: Cancer Research (2022)

Abstract Since the first immune checkpoint blocker Ipilimumab was approved by US FDA in 2011, more and more immune therapeutic drugs popped up. Humanized PBMC reconstitution in immune deficient mice is becoming a good model for evaluating therapeutic antibodies, especially the BsAb with one arm of anti-CD3 that mediates immune cells and another arm targeting a tumor antigen. However, limited window of dosing regimen triggered by graft-versus-host-disease (GvHD) after 30-40 days of reconstitution, and insufficient tumor-infiltrated immune cells naturally from reconstituted circulatory system hindered the widely application of the model in immunotherapy in development of multiple immune checkpoint inhibitors or immune agonists. To overcome this, LIDE has developed a unique human PBMC-cancer cells co-inoculated model instead. In our platform, cancer-priming PBMCs were mixed with the fresh cancer cells in MatriGel, co-inoculated into NCG mice to form a huPBMC well-infiltrated tumor tissue for immunotherapy. Our platform has been successfully helped evaluate biological function of PD1, Tigit, PVRIG, CD73, CD47, CD38, CD40, GITR Antibodies, Tgfb1/PDL1 BsAb, DLL3/CD3 BsAb in multiple cancers, such as melanoma, breast cancer and lung cancer. Citation Format: Bin Xie, Hongkui Chen, Xin Hou, Danyi Wen. PBMC humanized mouse model for ImmunoOncology drug evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1391.
Abstract 3062: Modifiable factors and gut microbiome alteration among colorectal cancer patients
Authors: Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Jeeyoo Lee, Aesun Shin
Journal: Cancer Research (2022)

Abstract Background: Previous study have indicated an association of microbial dysbiosis with stages of colorectal cancer (CRC). Meanwhile, higher microbial stochasticity has been introduced as the Anna Karenina principle (AKP) effect, which originates from the opening line of Leo Tolstoy and is translated in the microbiome as “all healthy microbiomes are similar; each dysbiotic microbiome is dysbiotic in its own way”. Here, we aim to elucidate the effect of modifiable factors on microbiome stochasticity related to dysbiosis in CRC. Methods: Fecal samples from 331 CRC patients, were collected prior to their surgery at Seoul National University Hospital. Bacteria that were enriched in early- and late-stage CRC groups were identified by linear discrimination analysis effect size (LEfSE) method, which was then used to calculate microbial dysbiosis index (MDI). The association of dietary choices with microbiome variability was addressed using the LEfSE analysis. The difference of intra-sample similarity index among lifestyle factors and metabolic diseases was tested to examine the AKP effect. A tree-based analysis of food choices was constructed. We then applied Procrustes framework to analyze the shape of dietary diversity and microbiome. Results: The LEfSE identified Leuconostoc, Oxalobacter, Acidaminococcus, and Methanobrevibacter were enriched in early-stage CRC, whereas Bacteroides, Fusobacterium, Lachnoanaerobaculum, Clostridium, and Granulicatella were enriched in late-stage CRC patients. The MDI derived from these bacteria had 64.2% predictive ability for CRC stages, with sensitivity and specificity of 61% and 69%, respectively. The AKP effect was found for history of smoking, alcohol consumption, and diabetes, whereas obesity and hypertension showed anti-AKP effect. For dietary choices, the hierarchical tree of foods and nutrients did not shape the microbial between-sample diversity. Additionally, high MDI was related with a high intake of pizza/hamburger, poultry, and light-vegetable combination. Conclusion: Our study contributed to current evidence of the microbiome structure and dysbiosis at different stages of CRC. Furthermore, history of smoking, alcohol consumption, and diabetes showed AKP effect in CRC patients. Non-significant association between dietary choices and microbiome diversity supported a small variation of microbiome profiles explained by dietary intake at the population level. Citation Format: Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Jeeyoo Lee, Aesun Shin. Modifiable factors and gut microbiome alteration among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3062.
Abstract 5611: CRB-601: A highly potent and selective integrin αvβ8 blocking antibody with anti-tumoral properties
Authors: Andrew Kolodziej, Eric Haines, Richard Morse, Eugene Zhukovsky
Journal: Cancer Research (2022)

Abstract TGFβ is a secreted protein produced by tumors that promotes cancer progression primarily via the suppression of both the innate and adaptive immune systems. This makes TGFβ a promising immunotherapeutic target in cancer. It is ubiquitously expressed in a latent (L-TGFβ) form and the latent form has been shown to promote an immune suppressive phenotype within the tumor microenvironment. Integrin αvβ8 specifically binds to L-TGFβ. This interaction is essential for the activation of L-TGFβ-mediated signals in a variety of immune cell types. Interestingly, it has been recently shown that integrin αvβ8-mediated TGFβ activation can active directly through L-TGFβ and does not require the release of active TGFβ (1). Inhibition of integrin αvβ8-mediated TGFβ activation has been shown to block immunosuppressive regulatory T cell differentiation and enhance the recruitment of cytotoxic T cells into the tumor microenvironment (2). Here, we demonstrate by Surface Plasmon Resonance (SPR) that CRB-601, our selective inhibitor of integrin αvβ8 monoclonal antibody candidate, has a high affinity and specificity for the integrin αvβ8 complex. Moreover, in comparison to competitor molecules, such as ADWA-11, CRB-601 substantially blocks TGFβ activation in a reporter cell assay system. Additionally, using syngeneic mouse models, we evaluated the anti-tumoral properties of CRB-601 as a monotherapy, as well as in combination with immune checkpoints therapies. Findings from this study highlight the importance of integrin αvβ8 blockade in mediating the immune landscape within the tumor and leads to an enhanced response to immune checkpoint therapy. In conclusion, CRB-601 is a potent and selective integrin αvβ8 blocking monoclonal antibody that enhances the activity of immune checkpoint inhibitors in vivo and holds promise as a potential combination partner for immunotherapy. Investigational New Drug (IND) enabling studies are currently underway. References: 1: Campbell MG. et al. (2020) Cyro-EM reveals integrin-mediated TGF-β activation without release from latent TGF-β. Cell 180, 490-501. 2: Mariathasan S. et al. (2018) TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544-48. Citation Format: Andrew Kolodziej, Eric Haines, Richard Morse, Eugene Zhukovsky. CRB-601: A highly potent and selective integrin αvβ8 blocking antibody with anti-tumoral properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5611.
Abstract 2316: Malignant potential of colorectal adenoma based on the telomere length
Authors: Kristyna Tomasova, Michal Kroupa, Anna Siskova, Josef Horak, Ondrej Vycital, Vaclav Liska, Ludmila Vodickova, Pavel Vodicka
Journal: Cancer Research (2022)

Abstract Telomere attrition is a well-known hallmark of malignancy in cancer tissue. Our study analyzed the relative telomere length in adenomas, precursor lesions of colorectal adenocarcinoma. We investigated if the accelerated telomere length shortening occurs before potential malignant transformation to adenocarcinoma and corresponds with clinicopathological characteristics. Relative telomere length was measured in 145 patients using multiplex qPCR. We have recorded significant shortening of telomeres in the adenoma tissue compared to adjacent mucosa (Wilcoxon Signed Rank test, p &amp;lt; 0.0001). Further, we have observed a weak inverse relationship between both adenoma and mucosa telomere length and age (Spearman's and Pearson's correlation, p = 0.021 and p = 0.027, respectively), contrary to our previous study of colorectal cancer patients (n = 696), where the inverse correlation of telomere length was detected only in the non-malignant mucosa (Pearson's correlation, p = 0.029). However, the telomere length ratio of adenoma to adjacent mucosa did not correspond with the degree of dysplasia according to the Vienna classification (Kruskal-Wallis test, p = 0.572). Also, there was no difference in the telomere length ratio among histological types of adenomas and no association with the adenoma localization in proximal and distal colon or rectum (Kruskal-Wallis test, p = 0.648 and p = 0.459, respectively). Preliminary results indicate that telomere shortening occurs indeed as early as in a stage of adenomatous polyps, and it is less pronounced in adenomas compared to cancerous cells. However, the relative telomere length does not seem to correspond with adenoma progression towards malignancy. In planned experiments, we intend to assess mitochondrial DNA damage caused by 8-oxoguanine DNA adducts. These major oxidative base lesions can arise from endogenous reactive oxygen species and impact, among other things, the integrity of telomeres through double-strand breaks to DNA. Mitochondrial DNA is more prone to accumulation of oxidative damage than nuclear DNA and thus might be useful as an early, additional indicator of the precancerous character of adenoma. The study will reveal whether increased mitochondrial DNA damage and telomere loss are commonly present and linked together in adenomas. This study was supported by the Charles University (project GA UK No. 120, UNCE/MED/006) and the Grant Agency of the Czech Republic (21-04607X, 21-27902S). Citation Format: Kristyna Tomasova, Michal Kroupa, Anna Siskova, Josef Horak, Ondrej Vycital, Vaclav Liska, Ludmila Vodickova, Pavel Vodicka. Malignant potential of colorectal adenoma based on the telomere length [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2316.
Abstract 6095: SMOC2 as a potential biomarker with diagnostic value in uterine leiomyosarcoma
Authors: Chen Cai, Raul Falcao, Georgia Kokaraki, Jorge Estefano Souza, Gustavo de Souza, Joseph Woodard Carlson, Tirzah Braz Petta
Journal: Cancer Research (2022)

Abstract Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignant tumor with poor prognosis. In contrast, uterine leiomyoma (uLM) is the most common benign tumor of the uterus found in women of reproductive age. Extracellular matrix (ECM) accumulation and remodeling are thought to be crucial for the development of these two tumors. To better understand the differences of ECM dynamics in these tumors, we have collected samples from 67 uLMS, 66 uLM and 68 normal myometrium (MM) which were analyzed by RNAseq (Illumina) and a high-resolution isoelectric focusing (HiRIEF) liquid chromatography-mass spectrometry (LC-MS)-based method (Dionex UltiMate™ 3000 RSLCnano System coupled to a Q-Exactive mass spectrometer, Thermo Scientific). After meta-analysis between uLM and uLMS groups using DESeq2 and edgeR, 112 genes were defined as common shared differentiatly expressed genes (DEG). Specific uLMS DEG were analyzed by gene ontology, KEGG pathway, and Reactome pathway. In the top 10 ranking of most affected biological processes/molecular functions/cellular components, we identified the gene SMOC2, a secreted calcium-binding protein of the BM-40/SPARC family which is present in the ECM and has been shown to be involved in fibrosis by modulating TGF-β1. SMOC2 is upregulated in uLM and is downregulated in both RNA and protein expression level in uLMS, compared to MM samples. We also observed that the TGFB1 pathway is downregulated in uLMS and upregulated in uLM, suggesting that this may induce high production of ECM which is related to fibrosis. In conclusion, this preliminary data shows SMOC2 as a potential biomarker to differentiate uLM and uLMS at the protein level and we plan to further study the role of SMOC2 in cell lines to improve our understanding on uLMS malignancy. Citation Format: Chen Cai, Raul Falcao, Georgia Kokaraki, Jorge Estefano Souza, Gustavo de Souza, Joseph Woodard Carlson, Tirzah Braz Petta. SMOC2 as a potential biomarker with diagnostic value in uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6095.
Covid-19: Omicron infection is poor booster to immunity, study finds
Authors: Jacqui Wise
Journal: BMJ (2022)

Covid-19: Omicron infection is poor booster to immunity, study finds Jacqui WisePeople infected with the omicron variant show poor immunity boosting against future covid-19 infection, researchers have found. 1 This may explain why breakthrough and repeat infections have been a common feature of the omicron wave of the pandemic, even among people who have been triple vaccinated, said the research team.Omicron is "an especially stealthy immune evader" said Danny Altmann, study coauthor from Imperial College London."Not only can it break through vaccine defences, it looks to leave very few of the hallmarks we'd expect on the immune system," he said."It's more stealthy than previous variants and flies under the radar, so the immune system is unable to remember it."The research team analysed blood samples from 731 UK healthcare workers who received three doses of mRNA vaccine and had different SARS-CoV-2 infection histories, to investigate antibody, T cell, and B cell immunity against omicron.The study, published in Science, 1 found that people with no prior SARS-CoV-2 infection who then had omicron showed enhanced cross reactive immunity to previous variants-with enhanced B and T cell immunity against the alpha, beta, gamma, and delta variants-but they showed reduced boosting against the omicron spike protein itself.1
Abstract 1107: Notch activation drives resistance to Kras(G12C) inhibition in lung adenocarcinoma
Authors: Elizabeth E. Hwang, Alex Lee, Stanley Leung, Marcus Breese, Alejandro Sweet-Cordero
Journal: Cancer Research (2022)

Abstract Approximately one-third of lung adenocarcinoma (LUAD) tumors contain driver mutations in the Kras GTPase, most commonly occurring as Kras(G12C) activating mutations. Despite the promising development of covalent G12C small molecule inhibitors, early-phase clinical trial data indicate most patients will likely demonstrate disease progression through either intrinsic or acquired resistance. Thus, there is an urgent need to identify such resistance mechanisms to targeting Kras. Our lab previously discovered a unique requirement for Notch3 in tumor-propagating cells from the KrasLSL-G12D p53fl/fl LUAD mouse model as well as in patient-derived xenografts. Here we report activated Notch3 as a novel driver of resistance to Kras(G12C) inhibition in LUAD cell lines. Aiming to study the Notch3 transcriptional signature in LUAD, we developed an inducible model of Notch3 intracellular domain (NICD) expression in Kras-mutant LUAD cell lines. Our data demonstrate that activated NICD modulates downstream RTK signaling pathways to suppress both cell cycle arrest and apoptosis in response to G12C inhibitor treatment. We subsequently performed RNA-sequencing to identify Notch-dependent genes driving resistance and in parallel, used Cut&amp;Run technology to interrogate the global chromatin binding profiles of Notch3 and associated histone marks in NICD-expressing cell lines. We integrate our transcriptomic and epigenomic data to reveal that NICD acts as a key regulator of Rho family genes, which in turn support cell survival upon Kras inhibition. We additionally find enrichment of cell division and morphological signatures in inhibitor treated NICD cell lines and we elucidate the mechanism of direct Notch target genes in mediating the apoptotic response. Finally, we conduct a focused in vitro CRISPRi screen in the H358 LUAD cell line to identify the subset of Notch target genes required for NICD-induced resistance. Our results define a Notch3 transcriptional landscape in LUAD and demonstrate a role for Notch signaling in promoting resistance to small molecule Kras inhibitors. Citation Format: Elizabeth E. Hwang, Alex Lee, Stanley Leung, Marcus Breese, Alejandro Sweet-Cordero. Notch activation drives resistance to Kras(G12C) inhibition in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1107.
Abstract 246: Application of the 3d fresh patient tumoroid platform 3d-explore to assess the immunomodulatory and phagocytic activity of the receptor tyrosine kinase inhibitor, Sunitinib
Authors: Brittany Bunch, Krithika N. Kodumudi, Jared Ehrhart, Matt Weitzman, Olivia MacIntosh, Kelly Sussman, Soner Altiok
Journal: Cancer Research (2022)

Abstract Background: The receptor tyrosine kinase inhibitor (TKI) Sunitinib has proven useful in the treatment of a variety of tumors. Sunitinib has shown therapeutic activity in patients with metastatic renal cell carcinoma and currently represents a frontline therapy for this disease. The immune modulatory effect of Sunitinib on immune cells within the tumor microenvironment has been well documented. Here, we developed a novel 3D ex-vivo platform (3D-EXplore) using fresh patient tumor samples with intact stromal components and tumor immune microenvironment to assess the therapeutic efficacy of Sunitinib. Methods: All tumor samples were obtained with patient consent and relevant IRB approval. Unpropagated 3D tumoroids with intact TME measuring 150 µm in size were prepared from fresh tumor samples of renal cell carcinoma using a proprietary technology developed at Nilogen Oncosystems. Tumoroids prepared from each patient’s tumor sample were pooled to represent the tumor heterogeneity and treated ex vivo with Sunitinib for 48h to detect treatment-mediated changes in tumor immune cell composition including CD4 and CD8 T-cells, NK cells, and macrophages. Additionally, we analyzed treatment-mediated changes in T-cell activation and phagocytic activity of myeloid cells. Results: Multiparameter flow analysis revealed that Sunitinib treatment led to an increase in CD8+CD25+ central memory-like phenotype and increased granzyme B expression in CD4 and CD8+ T cells indicating T cell activation. Furthermore, multiparameter flow cytometry analysis showed increased EdU uptake by CD8 and NK cells with sunitinib treatment, while cytokine release assays demonstrated increased IFN-γ and IL-2 production accompanied by downregulation of IL-10 and IL-6 cytokines. We observed Sunitinib mediated phagocytotic activity by tumor resident myeloid macrophages, monocytes, and dendritic cells using a quantitative phagocytosis assay. Conclusions: These results demonstrate that 3D-EXplore using fresh tumor samples provides a clinically relevant platform to assess drug response and serves as a critical tool for reflecting the true intact tumor microenvironment for novel immune-oncology drug development. Citation Format: Brittany Bunch, Krithika N. Kodumudi, Jared Ehrhart, Matt Weitzman, Olivia MacIntosh, Kelly Sussman, Soner Altiok. Application of the 3d fresh patient tumoroid platform 3d-explore to assess the immunomodulatory and phagocytic activity of the receptor tyrosine kinase inhibitor, Sunitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 246.
Abstract 1337: Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis
Authors: Jaideep Chakladar, Neil Shende, Wei Tse Li, Weg M. Ongkeko
Journal: Cancer Research (2022)

Abstract Background: Smoking remains a primary etiological agent of 12 different cancers. However, current understanding of the pathogenesis and progression of these smoking-induced cancers remains unclear. Though vaping has been proposed as a safer alternative to cigarette smoking, more research is needed to fully understand its potential to cause cancer. In particular, the chemicals in e-cigarette (e-cig) vapor have previously been demonstrated to cause immune dysregulation, similar to conventional cigarette smoke. In this study, we aimed to investigate the immune-associated (IA) genomic and transcriptomic landscapes of a panel of smoking-induced cancers in order to identify common and unique elements among these cancers and to determine whether certain immune dysregulations may be shared between smoking and vaping. Methods: Whole genome sequencing data from tumors and adjacent normal samples was obtained from The Cancer Genome Atlas (TCGA) to compare the IA landscapes of 5 different smoking-induced cancers: head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). Differentially expressed genes were identified and correlated to tumor stage and patient survival. Gene Set Enrichment Analysis and ReactomeFi were used to correlate IA gene expression to cancer pathway enrichment. The REVEALER algorithm was used to correlate gene expression to copy number variations and mutations. Results: We found that the genomic landscapes of smoking-induced cancers were largely unique. However, Osteopontin (OPN), an IA gene capable of regulating the EGFR and CD44 signaling cascades, was found to be upregulated along with its downstream targets in HNSCC, LUAD, LUSC, and ESCA smoking patients. Such upregulation was correlated to poorer prognosis for all 4 cancers. In vitro study indicated an upregulation of OPN and its downstream targets in cell lines exposed to both e-cig vapor and cigarette smoke. Conclusions: Despite few similarities among the IA landscapes of these smoking-induced cancers, we suggest the importance of OPN upregulation in HNSCC, LUSC, LUAD, and ESCA pathogenesis caused by smoking and, potentially, vaping. Citation Format: Jaideep Chakladar, Neil Shende, Wei Tse Li, Weg M. Ongkeko. Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1337.